US11318232B2 - Compositions and methods for delivering drugs to a vessel wall - Google Patents
Compositions and methods for delivering drugs to a vessel wall Download PDFInfo
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- US11318232B2 US11318232B2 US16/797,189 US202016797189A US11318232B2 US 11318232 B2 US11318232 B2 US 11318232B2 US 202016797189 A US202016797189 A US 202016797189A US 11318232 B2 US11318232 B2 US 11318232B2
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- RHTIPXQQAPLBDR-UHFFFAOYSA-N C.C.C.C.C.C.C.[H]N(CCCCCCN([H])C(=O)OCOC(=O)N([H])CN([H])C(C)=O)C(C)=O Chemical compound C.C.C.C.C.C.C.[H]N(CCCCCCN([H])C(=O)OCOC(=O)N([H])CN([H])C(C)=O)C(C)=O RHTIPXQQAPLBDR-UHFFFAOYSA-N 0.000 description 1
- AKMLGFILGSHNJK-UHFFFAOYSA-N CCCOC(=O)NC.COC(O)NCCCCCCOC=O Chemical compound CCCOC(=O)NC.COC(O)NCCCCCCOC=O AKMLGFILGSHNJK-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/08—Materials for coatings
- A61L29/085—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
- A61L29/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/10—Materials for lubricating medical devices
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2420/00—Materials or methods for coatings medical devices
- A61L2420/06—Coatings containing a mixture of two or more compounds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/48—Polyethers
- C08G18/4854—Polyethers containing oxyalkylene groups having four carbon atoms in the alkylene group
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/70—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the isocyanates or isothiocyanates used
- C08G18/72—Polyisocyanates or polyisothiocyanates
- C08G18/73—Polyisocyanates or polyisothiocyanates acyclic
Definitions
- the invention features balloon coatings and their use in delivering drugs to a vessel wall.
- coated balloon catheters for delivery of paclitaxel presents a number of technical challenges, including the problem of the transit-associated loss of paclitaxel which can arise in the process of the delivery of paclitaxel to a target site.
- the dominant design challenge for the success of drug-coated balloon technology is the development of a coating system with properties robust enough to physically maintain the agent on the surface of the balloon during transit of the device through the vascular system but still allow its rapid, uniform, efficient, and directed (i.e., with limited downstream distribution) transference to the vessel wall during balloon inflation (Gray and Granada, Circulation, 121:2672-2680 (2010)).
- the transit-associated loss of paclitaxel can occur during the passage of a coated balloon catheter from the point of entry into a blood vessel to arrival at the site where, and time when, the balloon is expanded to contact the vessel wall with the paclitaxel coating.
- the transit-associated loss of paclitaxel is undesirable for two reasons: (i) paclitaxel available at the target site is reduced by the transit-associated loss of paclitaxel, and (ii) paclitaxel is a cytotoxic agent making the systemic release into the blood stream undesirable.
- compositions of the invention feature formulations for coating balloons, and their use in drug delivery.
- the invention features a coating including: (i) from 3% to 35% (w/w) of a compound of formula (I) F T ⁇ [ B ⁇ (oligo)] n ⁇ B ⁇ G T (I), wherein B is a hard segment formed from hexamethylene diisocyanate, oligo is an oligomeric segment including polytetramethylene oxide, FT is a polyfluoroorgano group, and n is an integer from 1 to 10; and (ii) from 70% to 97% (w/w) crystalline paclitaxel dihydrate.
- the coating includes (i) from 15% to 25% (w/w) of the compound of formula (I) and (ii) from 75% to 85% (w/w) crystalline paclitaxel dihydrate.
- the polytetramethylene oxide has a molecular weight of from about 800 Da to 3,000 Da (e.g., from about 800 Da to 2,500 Da, about 800 Da to 2,000 Da, about 800 Da to 1,500 Da).
- the polyfluoroorgano group is a polyfluoroalkyl having a molecular weight of between 100-1,500 Da.
- the polyfluoroorgano group is a radical of the general formula CF 3 (CF 2 ) r CH 2 CH 2 — or CF 3 (CF 2 ) s (CH 2 CH 2 O) x —, wherein r is an integer from 2-20, x is an integer from 1-10, and s is an integer from 1-20.
- the polyfluoroorgano group is a radical of the general formula CH m F (3-m) (CF 2 ) r CH 2 CH 2 — or CH m F (3-m) (CF 2 ) s (CH 2 CH 2 O) x —, wherein m is 0, 1, 2, or 3; x is an integer between 1-10; r is an integer between 2-20; and s is an integer between 1-20.
- the polyfluoroorgano group is selected from (CF 3 )(CF 2 ) 5 CH 2 CH 2 O—, (CF 3 )(CF 2 ) 7 CH 2 CH 2 O—, (CF 3 )(CF 2 ) 5 CH 2 CH 2 O—, CHF 2 (CF 2 ) 3 CH 2 O—, and (CF 3 )(CF 2 ) 2 CH 2 O—, 1H,1H, 2H,2H-perfluoro-1-decanol; 1H,1H, 2H, 2H-perfluoro-1-octanol; 1H, 1H, 5H-perfluoro-1-pentanol; and 1H,1H, perfluoro-1-butanol, and mixtures thereof.
- the coating is a coating on at least a portion of a balloon catheter.
- the balloon catheter includes an energy generating element (e.g., an element that generates ultrasound, heat, electromagnetic, mechanical, or vibrational energy).
- the balloon catheter includes lithotripsy electrodes for deliverying ultrasonic energy to a vessel wall.
- the balloon catheter includes a mechanical energy generating element (e.g., wherein the balloon catheter is capable of scoring and/or cutting).
- the coating includes a paclitaxel concentration of from 1.0 ⁇ g/mm 2 to 6.0 ⁇ g/mm 2 (e.g., 1.5 ⁇ 0.5 ⁇ g/mm 2 , 2.5 ⁇ 0.5 ⁇ g/mm 2 , 3.0 ⁇ 0.5 ⁇ g/mm 2 , 3.5 ⁇ 0.5 ⁇ g/mm 2 , 4.0 ⁇ 0.5 ⁇ g/mm 2 , 4.5 ⁇ 0.5 ⁇ g/mm 2 , 5.0 ⁇ 0.5 ⁇ g/mm 2 , or 5.5 ⁇ 0.5 ⁇ g/mm 2 ).
- a paclitaxel concentration of from 1.0 ⁇ g/mm 2 to 6.0 ⁇ g/mm 2 (e.g., 1.5 ⁇ 0.5 ⁇ g/mm 2 , 2.5 ⁇ 0.5 ⁇ g/mm 2 , 3.0 ⁇ 0.5 ⁇ g/mm 2 , 3.5 ⁇ 0.5 ⁇ g/mm 2 , 4.0 ⁇ 0.5 ⁇ g/mm 2 , 4.5 ⁇ 0.5 ⁇ g/mm 2 , 5.0 ⁇ 0.5 ⁇ g/mm 2 , or 5.5 ⁇ 0.5
- the coating can have a thickness of from 0.01 to 250 microns (e.g., from 0.01 to 5 microns, 0.1 to 5 microns, 1 to 5 microns, 1 to 25 microns, 2 to 25 microns, 5 to 50 microns, 5 to 100 microns, 10 to 250 microns, 15 to 50 microns, or 20 to 125 microns).
- the coating can have a glass transition of from ⁇ 80 to 90° C. (e.g., from ⁇ 80 to 5° C., ⁇ 60 to 5° C., ⁇ 50 to 20° C., ⁇ 40 to 30° C., ⁇ 30 to 40° C., ⁇ 20 to 40° C., or 25 to 90° C.).
- the coating can have a tack of from 1.0 to 200 g (e.g., from 1.0 to 100 g, 1.0 to 50 g, 2.0 to 200 g, 2.0 to 100 g, 2.0 to 50 g, 1.0 to 25 g, 2.0 to 25 g, 3.0 to 75 g, 3.0 to 50 g, 3.0 to 25 g, or 1.0 to 20 g).
- the coating can have a viscosity of from 0.04 to 130 cps (e.g., from 20 to 130 cps, 50 to 130 cps, 75 to 130 cps, 0.04 to 30 cps, 0.04 to 70 cps, 0.5 to 130 cps, 0.5 to 13 cps, 0.5 to 30 cps, 0.5 to 70 cps, 1 to 130 cps, 1 to 20 cps, 1 to 50 cps, 5 to 25 cps, or 5 to 75 cps).
- 0.04 to 130 cps e.g., from 20 to 130 cps, 50 to 130 cps, 75 to 130 cps, 0.04 to 30 cps, 0.04 to 70 cps, 0.5 to 130 cps, 0.5 to 13 cps, 0.5 to 30 cps, 0.5 to 70 cps, 1 to 130 cps, 1 to 20 c
- the coating has a contact angle hysteresis of the surface of from 20-120° (e.g., from 20-60°, 30-70°, 40-80°, 60-90°, 70-100°, 80-110°, 90-120°, 60-120°, or 35-90°).
- the coatings of the invention can be formed by a method including the steps of: (x) dissolving the compound of formula (I) and paclitaxel in a mixture of an organic solvent and water to form a solution, (y) depositing the solution onto a surface, and (z) drying the surface to form the coating.
- the coating can be applied to the surface of the by solid deposition, spray coating, drop and drag coating, printing, or dip coating the surface with the solution.
- the organic solvent includes tetrahydrofuran, ethanol, acetone, heptane, hexane, methanol, ethyl acetate, toluene, isopropanol, or mixtures thereof.
- the solution can include from 0% to 20% (w/w) water (e.g., 1.0 ⁇ 0.5%, 2.5 ⁇ 1.0%, 5.0 ⁇ 2.0%, 7.0 ⁇ 1.5%, 8.0 ⁇ 2.0%, 12 ⁇ 2%, or 15 ⁇ 5% (w/w) water).
- the invention features a balloon catheter, wherein at least a portion of the surface of the balloon catheter includes a coating of the invention.
- the balloon catheter includes an energy generating element (e.g., an element that generates ultrasound, heat, electromagnetic, mechanical, or vibrational energy).
- the balloon catheter includes an ultrasound generating element (e.g., a lithotripsy electrode).
- the balloon catheter includes a mechanical energy generating element (e.g., wherein the balloon catheter is capable of scoring and/or cutting).
- the invention features a method of delivering paclitaxel to a vessel surface of a mammal, the method including contacting the vessel surface with a coating of the invention.
- the invention further features a method for inhibiting restenosis at a first site of a diseased vessel wall in a mammal in need thereof, the method including: (i) providing a balloon catheter, wherein at least a portion of the surface of the balloon catheter includes a coating of the invention; (ii) inserting the balloon catheter into a vessel of the mammal and delivering the balloon catheter to the first site of the vessel wall; and (iii) expanding the balloon to contact the coating to the first site and delivering the paclitaxel to the vessel wall.
- the balloon when expanded in water for 1 minute produces a cumulative count of fewer than 1,500 particles greater than 25 ⁇ m in diameter (e.g., fewer than 1,400 particles, 1,300 particles, 1,200 particles, or 1,000 particles greater than 25 ⁇ m in diameter).
- a porcine model from 75% to 95% (w/w) of the paclitaxel is retained on the balloon catheter prior to delivery to the vessel wall.
- in a porcine model from 45% to 65% (w/w) of the paclitaxel is retained on the balloon catheter immediately after delivery to the vessel wall.
- the method of inhibiting restenosis can further include: (iv) following step (iii) and prior to removing the balloon catheter from the vessel, contracting the size of the balloon; (v) moving the balloon to a second site of the diseased vessel wall; and (vi) expanding the balloon to contact the coating to the second site and delivering the paclitaxel to the vessel wall.
- the method can further include: (vii) following step (vi) and prior to removing the balloon catheter from the vessel, contracting the size of the balloon; (viii) moving the balloon to a third site of the diseased vessel wall; and (ix) expanding the balloon to contact the coating to the third site and delivering the paclitaxel to the vessel wall.
- the invention features a method for inhibiting restenosis at a first site of a calcified vessel wall in a mammal in need thereof, the method including: (i) providing a lithotripsy balloon catheter including one or more lithotripsy electrodes, wherein at least a portion of the surface of the lithotripsy balloon catheter includes a coating including crystalline paclitaxel dihydrate dispersed in a lipophilic carrier at a concentration of from 1.0 to 6.0 ⁇ g/mm 2 (e.g., 1.5 ⁇ 0.5 ⁇ g/mm 2 , 2.5 ⁇ 0.5 ⁇ g/mm 2 , 3.0 ⁇ 0.5 ⁇ g/mm 2 , 3.5 ⁇ 0.5 ⁇ g/mm 2 , 4.0 ⁇ 0.5 ⁇ g/mm 2 , 4.5 ⁇ 0.5 ⁇ g/mm 2 , 5.0 ⁇ 0.5 ⁇ g/mm 2 , or 5.5 ⁇ 0.5 ⁇ g/mm 2 PTX); (ii) inserting the balloon catheter into a vessel of the mammal and delivering the
- the coating includes 50% to 95% (w/w) (e.g., 55 ⁇ 5%, 65 ⁇ 5%, 75 ⁇ 5%, or 85 ⁇ 5% (w/w)) crystalline paclitaxel dihydrate and 5% to 50% (w/w) (e.g., 10 ⁇ 5%, 20 ⁇ 5%, 30 ⁇ 5%, or 40 ⁇ 5% (w/w)) butyryltrihexyl citrate.
- the coating includes 50% to 95% (w/w) (e.g., 55 ⁇ 5%, 65 ⁇ 5%, 75 ⁇ 5%, or 85 ⁇ 5% (w/w)) crystalline paclitaxel dihydrate and 5% to 50% (w/w) (e.g., 10 ⁇ 5%, 20 ⁇ 5%, 30 ⁇ 5%, or 40 ⁇ 5% (w/w)) acetyl tributyl citrate.
- the vessel can be a coronary vessel, an iliac vessel, or a peripheral vessel.
- the method can be performed as part of a surgical procedure selected from percutaneous translumenal angioplasty, coronary angioplasty, neurovascular angioplasty, balloon angioplasty for AV fistula and AV graft, or balloon aortic valvuplasty.
- the method is performed to inhibit restenosis at the site of an arteriovenous shunt.
- the invention features a coating including: (i) from 3% to 35% (w/w) of a compound of formula (I) F T ⁇ [ B ⁇ (oligo)] n ⁇ B ⁇ F T (I), wherein B is a hard segment formed from hexamethylene diisocyanate, oligo is an oligomeric segment including polytetramethylene oxide, FT is a polyfluoroorgano group, and n is an integer from 1 to 10; and (ii) from 70% to 97% (w/w) amorphous or crystalline rapamycin macrolide.
- the coating includes (i) from 5% to 25% (e.g., 15% to 25%) (w/w) of the compound of formula (I) and (ii) from 75% to 95% (e.g., 75% to 85%) (w/w) amorphous or crystalline rapamycin macrolide.
- the polytetramethylene oxide has a molecular weight of from about 800 Da to 3,000 Da (e.g., from about 800 Da to 2,500 Da, about 800 Da to 2,000 Da, about 800 Da to 1,500 Da).
- the amorphous or crystalline rapamycin macrolide is sirolimus.
- the polyfluoroorgano group is a polyfluoroalkyl having a molecular weight of between 100-1,500 Da.
- the polyfluoroorgano group is a radical of the general formula CF 3 (CF 2 ) r CH 2 CH 2 — or CF 3 (CF 2 ) s (CH 2 CH 2 O) x —, wherein r is an integer from 2-20, x is an integer from 1-10, and s is an integer from 1-20.
- the polyfluoroorgano group is a radical of the general formula CH m F (3-m) (CF 2 ) r CH 2 CH 2 — or CH m F (3-m) (CF 2 ) s (CH 2 CH 2 O) x —, wherein m is 0, 1, 2, or 3; x is an integer between 1-10; r is an integer between 2-20; and s is an integer between 1-20.
- the polyfluoroorgano group is selected from (CF 3 )(CF 2 ) 5 CH 2 CH 2 O—, (CF 3 )(CF 2 ) 7 CH 2 CH 2 O—, (CF 3 )(CF 2 ) 5 CH 2 CH 2 O—, CHF 2 (CF 2 ) 3 CH 2 O—, and (CF 3 )(CF 2 ) 2 CH 2 O—, 1H,1H,2H,2H-perfluoro-1-decanol; 1H,1H,2H,2H-perfluoro-1-octanol; 1H,1H,5H-perfluoro-1-pentanol; and 1H,1H, perfluoro-1-butanol, and mixtures thereof.
- the coating is a coating on at least a portion of a balloon catheter.
- the balloon catheter includes an energy generating element (e.g., an element that generates ultrasound, heat, electromagnetic, mechanical, or vibrational energy).
- the balloon catheter includes lithotripsy electrodes for deliverying ultrasonic energy to a vessel wall.
- the balloon catheter includes a mechanical energy generating element (e.g., wherein the balloon catheter is capable of scoring and/or cutting).
- the coating includes an amorphous or crystalline rapamycin macrolide concentration of from 1.0 ⁇ g/mm 2 to 10.0 ⁇ g/mm 2 (e.g., 1.5 ⁇ 0.5 ⁇ g/mm 2 , 2.5 ⁇ 0.5 ⁇ g/mm 2 , 3.0 ⁇ 0.5 ⁇ g/mm 2 , 3.5 ⁇ 0.5 ⁇ g/mm 2 , 4.0 ⁇ 0.5 ⁇ g/mm 2 , 4.5 ⁇ 0.5 ⁇ g/mm 2 , 5.0 ⁇ 0.5 ⁇ g/mm 2 , 5.5 ⁇ 0.5 ⁇ g/mm 2 , 6.0 ⁇ 0.5 ⁇ g/mm 2 , 6.5 ⁇ 0.5 ⁇ g/mm 2 , 7.0 ⁇ 0.5 ⁇ g/mm 2 , 7.5 ⁇ 0.5 ⁇ g/mm 2 , 8.0 ⁇ 0.5 ⁇ g/mm 2 , 8.5 ⁇ 0.5 ⁇ g/mm 2 , 9.0 ⁇ 0.5 ⁇ g/mm 2 , or 9.5 ⁇ 0.5 ⁇ g/mm 2 ).
- amorphous or crystalline rapamycin macrolide concentration of from
- the amorphous or crystalline rapamycin macrolide concentration is from 1.0 ⁇ g/mm 2 to 6.0 ⁇ g/mm 2 (e.g., 1.5 ⁇ 0.5 ⁇ g/mm 2 , 2.5 ⁇ 0.5 ⁇ g/mm 2 , 3.0 ⁇ 0.5 ⁇ g/mm 2 , 3.5 ⁇ 0.5 ⁇ g/mm 2 , 4.0 ⁇ 0.5 ⁇ g/mm 2 , 4.5 ⁇ 0.5 ⁇ g/mm 2 , 5.0 ⁇ 0.5 ⁇ g/mm 2 , or 5.5 ⁇ 0.5 ⁇ g/mm 2 ).
- the coating can have a thickness of from 0.01 to 250 microns (e.g., from 0.01 to 5 microns, 0.1 to 5 microns, 1 to 5 microns, 1 to 25 microns, 2 to 25 microns, 5 to 50 microns, 5 to 100 microns, 10 to 250 microns, 15 to 50 microns, or 20 to 125 microns).
- the coating can have a glass transition of from ⁇ 80 to 90° C. (e.g., from ⁇ 80 to 5° C., ⁇ 60 to 5° C., ⁇ 50 to 20° C., ⁇ 40 to 30° C., ⁇ 30 to 40° C., ⁇ 20 to 40° C., or 25 to 90° C.).
- the coating can have a tack of from 1.0 to 200 g (e.g., from 1.0 to 100 g, 1.0 to 50 g, 2.0 to 200 g, 2.0 to 100 g, 2.0 to 50 g, 1.0 to 25 g, 2.0 to 25 g, 3.0 to 75 g, 3.0 to 50 g, 3.0 to 25 g, or 1.0 to 20 g).
- the coating can have a viscosity of from 0.04 to 130 cps (e.g., from 20 to 130 cps, 50 to 130 cps, 75 to 130 cps, 0.04 to 30 cps, 0.04 to 70 cps, 0.5 to 130 cps, 0.5 to 13 cps, 0.5 to 30 cps, 0.5 to 70 cps, 1 to 130 cps, 1 to 20 cps, 1 to 50 cps, 5 to 25 cps, or 5 to 75 cps).
- 0.04 to 130 cps e.g., from 20 to 130 cps, 50 to 130 cps, 75 to 130 cps, 0.04 to 30 cps, 0.04 to 70 cps, 0.5 to 130 cps, 0.5 to 13 cps, 0.5 to 30 cps, 0.5 to 70 cps, 1 to 130 cps, 1 to 20 c
- the coating has a contact angle hysteresis of the surface of from 20-120° (e.g., from 20-60°, 30-70°, 40-80°, 60-90°, 70-100°, 80-110°, 90-120°, 60-120°, or)35-90°.
- the coatings of the invention can be formed by a method including the steps of: (x) dissolving the compound of formula (I) and rapamycin macrolide in a mixture of an organic solvent and water to form a solution, (y) depositing the solution onto a surface, and (z) drying the surface to form the coating.
- coatings of the invention can be formed by a method comprising the steps of: (x) dissolving the compound of formula (I) in an organic solvent and adding to crystalline rapamycin macrolide to form a suspension, (y) depositing the suspension onto a surface, and (z) drying the surface to form the coating.
- the drying process increases rapamycin macrolide crystallinity prior to sterilization.
- sterilization or exposure to humidity can increase rapamycin macrolide crystalline.
- the coating can be applied to the surface of the by solid deposition, spray coating, drop and drag coating, printing, or dip coating the surface with the solution.
- the organic solvent includes methyl tert-butyl ether, tetrahydrofuran, ethanol, acetone, heptane, hexane, methanol, ethyl acetate, toluene, isopropanol, or mixtures thereof.
- the solution can include from 0% to 20% (w/w) water (e.g., 1.0 ⁇ 0.5%, 2.5 ⁇ 1.0%, 5.0 ⁇ 2.0%, 7.0 ⁇ 1.5%, 8.0 ⁇ 2.0%, 12 ⁇ 2%, or 15 ⁇ 5% (w/w) water).
- the invention features a balloon catheter, wherein at least a portion of the surface of the balloon catheter includes a coating of the invention.
- the balloon catheter includes an energy generating element (e.g., an element that generates ultrasound, heat, electromagnetic, mechanical, or vibrational energy).
- the balloon catheter includes an ultrasound generating element (e.g., a lithotripsy electrode).
- the balloon catheter includes a mechanical energy generating element (e.g., wherein the balloon catheter is capable of scoring and/or cutting).
- the invention features a method of delivering rapamycin macrolide to a vessel surface of a mammal, the method including contacting the vessel surface with a coating of the invention.
- the invention further features a method for inhibiting restenosis at a first site of a diseased vessel wall in a mammal in need thereof, the method including: (i) providing a balloon catheter, wherein at least a portion of the surface of the balloon catheter includes a coating of the invention; (ii) inserting the balloon catheter into a vessel of the mammal and delivering the balloon catheter to the first site of the vessel wall; and (iii) expanding the balloon to contact the coating to the first site and delivering the rapamycin macrolide to the vessel wall.
- the balloon when expanded in water for 1 minute produces a cumulative count of fewer than 1,500 particles greater than 25 ⁇ m in diameter (e.g., fewer than 1,400 particles, 1,300 particles, 1,200 particles, or 1,000 particles greater than 25 ⁇ m in diameter).
- a porcine model from 75% to 95% (w/w) of the rapamycin macrolide is retained on the balloon catheter prior to delivery to the vessel wall.
- in a porcine model from 10% to 65% (w/w) (e.g., 45% to 65% (w/w)) of the rapamycin macrolide is retained on the balloon catheter immediately after delivery to the vessel wall.
- the method of inhibiting restenosis can further include: (iv) following step (iii) and prior to removing the balloon catheter from the vessel, contracting the size of the balloon; (v) moving the balloon to a second site of the diseased vessel wall; and (vi) expanding the balloon to contact the coating to the second site and delivering the rapamycin macrolide to the vessel wall.
- the method can further include: (vii) following step (vi) and prior to removing the balloon catheter from the vessel, contracting the size of the balloon; (viii) moving the balloon to a third site of the diseased vessel wall; and (ix) expanding the balloon to contact the coating to the third site and delivering the rapamycin macrolide to the vessel wall.
- the invention features a method for inhibiting restenosis at a first site of a calcified vessel wall in a mammal in need thereof, the method including: (i) providing a lithotripsy balloon catheter including one or more lithotripsy electrodes, wherein at least a portion of the surface of the lithotripsy balloon catheter includes a coating including crystalline rapamycin macrolide dispersed in a lipophilic carrier at a concentration of from 1.0 ⁇ g/mm 2 to 10.0 ⁇ g/mm 2 (e.g., 1.5 ⁇ 0.5 ⁇ g/mm 2 , 2.5 ⁇ 0.5 ⁇ g/mm 2 , 3.0 ⁇ 0.5 ⁇ g/mm 2 , 3.5 ⁇ 0.5 ⁇ g/mm 2 , 4.0 ⁇ 0.5 ⁇ g/mm 2 , 4.5 ⁇ 0.5 ⁇ g/mm 2 , 5.0 ⁇ 0.5 ⁇ g/mm 2 , 5.5 ⁇ 0.5 ⁇ g/mm 2 , 6.0 ⁇ 0.5 ⁇ g/mm 2 , 6.5 ⁇ 0.5 ⁇ g
- the crystalline rapamycin macrolide is dispersed in the liphophilic carrier at a concentration of from 1.0 ⁇ g/mm 2 to 6.0 ⁇ g/mm 2 (e.g., 1.5 ⁇ 0.5 ⁇ g/mm 2 , 2.5 ⁇ 0.5 ⁇ g/mm 2 , 3.0 ⁇ 0.5 ⁇ g/mm 2 , 3.5 ⁇ 0.5 ⁇ g/mm 2 , 4.0 ⁇ 0.5 ⁇ g/mm 2 , 4.5 ⁇ 0.5 ⁇ g/mm 2 , 5.0 ⁇ 0.5 ⁇ g/mm 2 , or 5.5 ⁇ 0.5 ⁇ g/mm 2 ).
- 1.0 ⁇ g/mm 2 to 6.0 ⁇ g/mm 2 e.g., 1.5 ⁇ 0.5 ⁇ g/mm 2 , 2.5 ⁇ 0.5 ⁇ g/mm 2 , 3.0 ⁇ 0.5 ⁇ g/mm 2 , 3.5 ⁇ 0.5 ⁇ g/mm 2 , 4.0 ⁇ 0.5 ⁇ g/mm 2 , 4.5 ⁇ 0.5 ⁇ g/mm 2 , 5.0 ⁇ 0.5 ⁇ g/mm 2 , or
- the coating includes 50% to 95% (w/w) (e.g., 55 ⁇ 5%, 65 ⁇ 5%, 75 ⁇ 5%, or 85 ⁇ 5% (w/w)) crystalline rapamycin macrolide and 5% to 50% (w/w) (e.g., 10 ⁇ 5%, 20 ⁇ 5%, 30 ⁇ 5%, or 40 ⁇ 5% (w/w)) butyryltrihexyl citrate.
- the coating includes 50% to 95% (w/w) (e.g., 55 ⁇ 5%, 65 ⁇ 5%, 75 ⁇ 5%, or 85 ⁇ 5% (w/w)) crystalline rapamycin macrolide and 5% to 50% (w/w) (e.g., 10 ⁇ 5%, 20 ⁇ 5%, 30 ⁇ 5%, or 40 ⁇ 5% (w/w)) acetyl tributyl citrate.
- the vessel can be a coronary vessel, an iliac vessel, or a peripheral vessel.
- the method can be performed as part of a surgical procedure selected from percutaneous translumenal angioplasty, coronary angioplasty, neurovascular angioplasty, balloon angioplasty for AV fistula and AV graft, or balloon aortic valvuplasty.
- the method is performed to inhibit restenosis at the site of an arteriovenous shunt.
- the rapamycin macrolide can be selected from sirolimus, zotarolimus, everolimus, temsirolimus, ridaforolimus, umirolimus, and biolimus.
- the tack of a coating of the invention can be measured, for example, using a TA.XTPlus Texture Analyser (Stable Micro Systems; distributed by Texture Technologies Corp; Scarsdale, N.Y.), which measures tack in “grams of force”.
- TA.XTPlus Texture Analyser Stable Micro Systems; distributed by Texture Technologies Corp; Scarsdale, N.Y.
- inhibiting restenosis refers to reducing the re-narrowing of artries following treatment to clear the blockage, such as angioplasty, using a therapy of the invention in comparison to the re-narrowing that would occur following treatment to clear the blockage in the absence of any further therapy to address the risk of restenosis.
- the term “cumulative count” refers to the numbers of particles produced by a balloon coated with 3.0 ⁇ g/mm 2 PTX using the method described in Example 14.
- rapamycin macrolide refers to rapamycin (also referred to as sirolimus) as well as other macrolide structural analogues of rapamycin which are inhibitors of the mTOR cellular signaling pathway, and preferably inhibitors of mTOR itself.
- Rapamycin macrolides include everolimus (Affinitor; RAD001), temsirolimus (CCI-779), ridaforolimus (previously known as deforolimus; AP23573), umirolimus (Biolimus A9), zotarolimus (ABT-578), novolimus, myolimus, AP23841, KU-0063794, INK-128, EX2044, EX3855, EX7518, AZD08055 and OSI027.
- Formulation 1 was prepared as described in Example 7.
- Formulation 2 was prepared as described in Example 8.
- FIG. 3 is an SEM image of Formulation 1 coated onto balloon as described in Example 11. The image depicts crystals of PTX dijuste in the coating.
- FIG. 4 is an SEM image of Formulation 2 coated onto balloon as described in Example 12. The image depicts crystals of PTX dijuste in the coating.
- FIGS. 5A-5D are SEM and optical images of Formulation 1 on nylon and Pebax balloons prepared as described in Example 13.
- FIG. 6 is a graph depicting the cumulative number of particles formed from balloons bearing different PTX coatings following exposure to water in a beaker as described in Example 14.
- the following coatings were tested: (a) Formulation 1 coated onto a Nylon 12 balloon catheter; (b) Formulation 1 coated onto a Pebax balloon catheter; (c) IN.PACTTM AdmiralTM drug coated balloon catheter; and (d) Lutonix® 035 drug coated balloon PTA catheter.
- the coatings made from Formulaion 1 exhibit a dramatic reduction in particle counts compared to the IN.PACTTM AdmiralTM and Lutonix® 035 balloons.
- FIG. 7 is a graph depicting the post treatment PTX retention for different balloon coatings in a flow loop model as described in Example 16.
- FIG. 8 is a graph depicting the post single treatment with shockwave PTX retention for different balloon coatings in a flow loop model as described in Example 17.
- FIG. 9 is a graph depicting the pre-deployment PTX loss in transit for different balloon coatings in a porcine model as described in Example 18.
- FIG. 10 is a graph depicting the post-deployment (post-inflation) PTX loss for different balloon coatings in a porcine model as described in Example 19.
- FIG. 11 is a graph depicting the PTX retention for Formulation 1 post multiple inflation and lithotripsy treatments in a porcine model as described in Example 20.
- FIG. 12 is a graph depicting the segmentation of balloon treated vessel during necropsy as described in Example 21.
- FIG. 13 is a graph depicting the median level of paclitaxel (PTX) in vessels following treatment with different coatings as described in Example 23.
- the median level of paclitaxel (PTX) in vessels treated with Formulation 1 (7.2 ⁇ g PTX/g of vessel) were double that of Pantera Lux (3.15 ⁇ g PTX/g of vessel), while the median level of PTX observed for Formulation 3 (0.04 ⁇ g PTX/g of vessel) and Formulation 4 ( ⁇ 0.01 ⁇ g PTX/g of vessel) delivered the lowest median levels of PTX to vessels.
- FIG. 14 is a graph depicting the amount of paclitaxel (PTX) delivered to the heart of in a porcine study as described in Example 23. It was observed that PTX was delivered at a consistently high dose to Formulation 1-treated hearts in comparison to other formulations. Each bar of the graph represents a given heart; there were three total hearts per group.
- PTX paclitaxel
- FIG. 15 are a series of SEM images of Formulation 9 coated PTCA and PTA balloon catheters.
- FIG. 16 are a series of SEM images of Formulation 9 coated PTCA balloon catheters subject to various drying processes immediately after coating.
- FIG. 17 is a graph depicting sirolimus release in PBS tween buffer of Formulation 9 from Nylon 12 coupons after 24 hours.
- FIG. 18 is a graph depicting drug retention for Formulation 9 coated PTA balloon catheters compared to Formulation 1 coated Nylon 12 PTA balloon catheter, Formulation 1 coated Pebax PTA lithotripsy catheter, and competitor benchmarks Lutonix®, IN.PACTTM, RangerTM, and StellarexTM
- FIG. 19 is a graph depicting drug retention for Formulation 9 coated on Nylon 12 PTCA balloon catheter compared to Magic Touch drug-eluting balloon and Formulation 1 coated Nylon 12 PTCA balloon.
- the methods and compositions of the invention feature coatings including a compound of formula (I): F T ⁇ [ B ⁇ (oligio)] n ⁇ B ⁇ F T (I), wherein B is a hard segment formed from hexamethylene diisocyanate, oligo is an oligomeric segment including polytetramethylene oxide, FT is a polyfluoroorgano group, and n is an integer from 1 to 10; and (ii) crystalline paclitaxel dihydrate or a rapamycin macrolide.
- the coatings of the invention do not have the properties of a base polymer, they are not susceptible to flaking or cracking during the physical manipulation of the device, such as the expansion and deployment of a balloon catheter.
- the coatings of the invention can control the release of paclitaxel or rapamycin macrolide incorporated within the coating by limiting the rate of diffusion of the agent from the coating prior to disruption of the coating (e.g., by deformation of the coating, or by exposing the coating to an energy source).
- a primary function of such coating can be to increase efficacy of local delivery of paclitaxel or a rapamycin macrolide for a defined period of time.
- the coatings of the invention can be applied to the surface of a balloon catheter in any number of ways including, but not limited, to electrodeposition, dipping, drag coating, spraying, brushing, printing, or spin coating of the coating material from a solution or suspension followed by solvent removal step as needed. Further description of how the coatings can be made and applied is found in the Examples.
- Vascular stenotic/occlusive diseases are mainly caused by changes in pathophysiobiology of the vasculature, resulting in thickening of the vessel lining from fatty deposits or plaques.
- the most popular mode of therapy for vascular occlusive diseases is the surgical bypass.
- endovascular interventions have been recognized and practiced as an alternative and viable mode of therapy.
- Balloon angioplasty is designed to expand occluded blood vessels based on balloon inflation, and compression of plaque, allowing perfusion of the diseased tissue.
- a guiding catheter is advanced in the patient's vasculature until the distal tip of the guiding catheter is located close to the targeted location.
- a guidewire is advanced out of the distal end of the guiding catheter into the patient's blood vessel, until the distal end of the guidewire crosses a lesion to be dilated.
- a dilation catheter having an inflatable balloon on the distal portion thereof is advanced into the patient's blood vessel over previously introduced guidewire until the balloon of the dilatation catheter is properly positioned across the lesion.
- the success of the endovascular intervention is generally high, but the vessel patency is often reduced due to restenosis in the vicinity of the original lesion causing re-occlusion of the vessel.
- the ability to locally deliver pharmaceuticals from a balloon surface provides an approach in controlling restenosis.
- the entire or partial external balloon surface can be coated with a desired pharmaceutical, the time of balloon inflation or the multiplicity of inflation can also be controlled, making the “drug eluting balloon” an adaptable and robust tool for local drug delivery.
- compositions and methods of this invention can be used in various applications of drug eluting balloon technology, such as percutaneous translumenal angioplasty (PTA), coronary angioplasty (PTCA), neurovascular angioplasty (PTNA), balloon aortic valvuplasty (BAV).
- PTA percutaneous translumenal angioplasty
- PTCA coronary angioplasty
- PTNA neurovascular angioplasty
- BAV balloon aortic valvuplasty
- the composition of the invention allows incorporation of various biological agents depending on the application of the drug eluting balloons.
- DEB can also be used as balloon aortic valvuplasty to repair stenotic aortic valve which has become stiff from calcium buildup.
- the balloon is inserted and inflated into the aortic valve to increase the opening size of the valve and improving blood flow.
- Traditional balloon aortic valvuloplasty many times fails to prevent restenosis in patients.
- Drug eluting balloon in this case allows the incorporated antirestenotic drug to elute into dilated aortic valves to prevent restenosis post-treatment.
- DEB can be used to treat coronary and peripheral diseases which are not treatable by stenting. This is particularly true for vessels below the knee in which the vessels are small and the stent struts break under the torque. Additionally, DEB may be used to treat in-stent restenosis. In another example, DEB can be used to treat coronary and peripheral diseases in combination with a stent.
- Balloon catheter can be coated with anticancer agent and introduced to cancerous tissue.
- a drug eluting balloon may also be used in the nasal cavity and can be used for treating, e.g., chronic sinusitis, such as by coating the DEB with a rapamycin macrolide.
- Balloons for angioplasty are categorized as high pressure balloons.
- a standard balloon consists of a cylindrical body, two conical tapers, and two necks. The particular angles and shapes of the balloon can be customized depending on the application and particularities of the physiology.
- High pressure balloons are also used to dilate constrictions and blockages in other areas such as the esophagus, biliary-duct, urethra, fallopian-tube, heart-valve, tear-duct and carpel-tunnel dilation.
- Other applications for high pressure balloons include positioning, occlusion, light therapy, heat transfer and endovascular graft delivery.
- High pressure balloons are made from noncompliant or low-compliant materials (expand only 5-10%) which have controllable size and shape. Thin-walled, these balloons exhibit high tensile strength with relatively low elongation.
- PET has high tensile strength with a maximum pressure rating. It can be molded to have ultra thin walls (5-50 mm) with diameters from 0.5-50 mm.
- Nylon is softer and can be easily refolded for easier withdrawal into the guiding catheter. Both materials have demonstrated compatibility to coatings which provide lubricity, abrasion and puncture resistance, conductivity, thrombogenicity, drug release, and reflectivity, among other characteristics.
- the rated pressure for angioplasty is 2-20 atm. Larger diameter balloons have a lower rated pressure as the stress in the balloon wall increases when inflated to the nominal diameter.
- PTCA balloon catheters are usually 2-4 mm in diameter, 10-40 mm in length and have a rate pressure of 10-20 atm.
- PTA balloon catheters are usually 4-14 mm in diameter and 20-200 mm in length and have a rate pressure of 8-20 atm.
- a wide variety of balloon catheters can be coated using the compositions and methods of the invention to deliver paclitaxel or a rapamycin macrolide at a desired site of treatment.
- the balloon catheters of the invention can include energy sources including ultrasound, heat, electromagnetic, mechanical, and/or vibrational energy sources for disrupting the coating and releasing the paclitaxel or a rapamycin macrolide.
- an ultrasound external energy source may be used having a frequency in a range from 20 kHz to 100 MHz, preferably in a range from 0.1 MHz to 20 MHz, and an intensity level in a range from 0.05 W/cm 2 to 10 W/cm 2 , preferably in a range from 0.5 W/cm 2 to 5 W/cm 2 .
- the ultrasound energy would be directed at the coating and either continuously applied or pulsed, for a time period in a range from 5 seconds to 10 minutes, preferably in a range from 1 minute to 3 minutes.
- the temperature of the surface of the balloon catheter can be heated (e.g., in the range of from 36° C. to 48° C.), vibrated, or subjected to electromagnetic energy to facilitate the release of paclitaxel or a rapamycin macrolide at the desired place and time.
- the balloon catheter includes razor blades, struts, or pull wires that are capable of scoring and/or cutting.
- DBTDL dibutyltin dilaurate
- the reaction mixture was stirred over night at 45° C. to produce the desired fluorinated polymers.
- the polymer was precipitated in deionized water under constant stirring. The Volume of water used for the precipitation should be approximately 3.3 times the volume of the DMAc solvent in the solution.
- the polymer was purified by dissolution in boiling isopro panol, followed by cooling to 50-60° C., and precipitation by slow addition of hexane. The precipitated polymer was collected on a filter and washed with hexane. The purified poly mer was dried in a convection oven at 50° C. for at least 48 hours to produce compound 1 (general formula depicted below).
- MePEG (15.0 g, 20 mmol) was degassed and then dissolved in DMAc (243 mL), and added dropwise into LDI-methyl (8.48 g, 40 mmol) in DMAc (49 mL) in the presence of DBDL catalyst, at 40° C. over 3 hours under N 2 .
- Perfluoroalcohol (24.024 g, 66 mmol) was degased and added to the reaction with present of DBDL catalyst, and stirred at room temperature overnight under N 2 .
- the product was purified by cationic SPE and solvent extraction (Compound 2) (general formula depicted below).
- Compound 1 from Example 1 was weighed into polypropylene conical tubes capped with lint-free tissue, placed in sterilization pouches, and were sterilized by EtO. The sterilized compositions were analyzed by GPC, NMR and DSC. Results were compared to the pre-sterilization profile. No changes were observed for pre and post sterilization sample.
- Balloon catheters coated with Compound 1+ PTX (paclitaxel) dihydrate crystals were also sterilized by EtO. Sterilized and non-sterilized balloon catheters were analyzed by HPLC, and PTX retention time pre and post sterilization compared. PTX HPLC retention time (min): Pre-sterilization: 11.165 (PTX control: 11.163), post sterilization: 10.84 (PTX control: 10.84). Visually, coatings were similar pre and post sterilization with no additional features noted.
- Compound 1 was prepared using an extraction ratio of 6 cm 2 /1 mL 31.6 cm 2 of test article was extracted in 5.3 mL of Eagle's minimum essential medium (E-MEM)+5% fetal bovine serum (FBS). Samples were extracted at 37 ⁇ 1° C. for 24 ⁇ 2 hours. The extract was inoculated onto the cell line and incubated at 37 ⁇ 1° C. in a humidified atmosphere with 5 ⁇ 1% CO 2 in the air. Positive and negative controls were run in parallel with the test article. Cultures were evaluated for cytotoxic effects by microscopic observation after 24, 48 and 72 hour incubation periods. The test article passes and is considered non-cytotoxic under the test conditions employed.
- E-MEM Eagle's minimum essential medium
- FBS fetal bovine serum
- Formulation 2 was dissolved in 1:1 acetone:ethanol with 5% (w/w) water and the resulting solution was immediately coated onto 5.0 ⁇ 40 mm Nylon 12 PTA balloon catheters by an in-house drop and drag coater and dried overnight to form a coating containing 3.0 ⁇ g/mm 2 PTX. SEM images of all coated balloons displayed crystalline drug coatings (see FIG. 4 ).
- Formulation 1 was coated on Nylon 12 and Pebax based PTA balloon catheters using established drop and drag coating methods. Optical microscopy and SEM showed similar coating morphology with crystalline drug coatings on both Nylon 12 and Pebax balloons (see FIGS. 5A-5D ).
- a suitable apparatus was used based on the principle of lightblockage that allows for an automatic determination of the size of particles and the number of particles according to size.
- the apparatus is calibrated using dispersions of spherical particles of known sizes between 10 mm and 25 mm. These standard particles were dispersed in particle-free water. Care was taken to avoid aggregation of particles during dispersion.
- Formulation 1 was coated on Nylon 12 and Pebax balloon catheters to form a coating containing 3 ⁇ g/mm 2 paclitaxel. Coated balloon catheters were exposed to water in a beaker to nominal pressure and held for 1 minute. Water after inflation was analyzed by the particle counter APSS-2000, ⁇ 788> as a general guideline. The cumulative number of particles were measured for (i) Formulation 1 on a 5 ⁇ 60 mm Nylon 12 balloon catheter (>10 ⁇ m: 5117, >25 ⁇ m: 664) and (ii) for Formulation 1 on a 5 ⁇ 60 mm Pebax balloon catheter (>10 ⁇ m: 3146, >25 ⁇ m: 371).
- Formulation 3 was coated on 5 ⁇ 60 mm Nylon 12 balloon catheters to form a coating containing 3 ⁇ g/mm 2 paclitaxel. Coated balloon catheters were exposed to water in a beaker to nominal pressure and held for 1 minute. Water after inflation was analyzed by the particle counter APSS-2000, ⁇ 788> as a general guideline.
- the cumulative number of particles were measured for Formulation 3 on a Nylon 12 balloon catheter (>10 ⁇ m: 2204, >25 ⁇ m: 419).
- Phosphate buffered saline at 37° C. was pumped by a peristaltic pump through silicone tubing connections.
- the pump flow rate was set similar to the rate of blood flow through femoral arteries (350 mL/min).
- a Nylon 12 PTA balloon catheter coated with Formulation 1 was placed in the middle of the buffer flow for 2 minutes.
- the PTX remaining on the balloon catheter was measured by stripping the coating and quantified using RP-HPLC with benzonitrile as the internal standard. The % PTX remaining was observed to be 95.7%.
- Formulation 2 was tested under the same conditions and the % PTX remaining was observed to be 58%.
- Phosphate buffered saline at 37° C. was pumped by a peristaltic pump through silicone tubing connections.
- the pump flow rate was set similar to the rate of blood flow through femoral arteries (350 mL/min).
- a Nylon 12 PTA balloon catheter coated with Formulation 1 was tracked through the silicone tubing under flow, then inflated to establish contact with the silicone tubing. Once inflated, the balloon was held in place for 1 minute, then deflated and removed from the tubing.
- PTX remaining on the balloon was measured by stripping the coating and quantified using RP-HPLC with benzonitrile as the internal standard. The % PTX remaining was observed to be 70.4%.
- the amount of PTX remaining on the balloon coated with Formulation 1 was higher than that of the IN.PACTTM model (in house proxy, the % PTX remaining was observed to be 38%—see FIG. 7 ).
- Formulation 1 post balloon deployment suggest that deployment of the balloon at the treatment site does not compromise the the ability of Formulation 1 to resist loss of PTX after a treatment event.
- Phosphate buffered saline at 37° C. was pumped by a peristaltic pump through silicone tubing connections.
- the pump flow rate was set similar to the rate of blood flow through femoral arteries (350 mL/min).
- a Nylon 12 PTA balloon catheter coated with Formulation 1 was tracked through the silicone tubing under flow, then inflated to establish contact with the silicone tubing. Once inflated, the PTA balloon was held in place for 1 minute, then deflated, tracked to a second location and inflated to establish contact with the silicone tubing; the two locations were non-overlapping. The balloon was held inflated in the second position for 1 minute, then deflated and removed from the tubing.
- PTX remaining on the Nylon 12 PTA balloon was measured by stripping the coating and quantified using RP-HPLC with benzonitrile as the internal standard. The % PTX retention was 59%.
- a Pebax PTA lithotripsy catheter coated with Formulation 1 was tracked through the silicone tubing under flow, then inflated to establish contact with the silicone tubing.
- a mock lithotripsy treatment was initiated, consisting of an acoustic shock sequence with a 1 minute duration.
- the PTA balloon was deflated, tracked to a second location and inflated to establish contact with the silicone tubing, at which point a second 1 minute-long mock lithotripsy treatment was performed; the two locations were non-overlapping.
- the PTA balloon was deflated and removed from the tubing.
- PTX remaining on the Pebax PTA balloon was measured by stripping the coating and quantified using RP-HPLC with benzonitrile as the internal standard. The % PTX retention was 50%. The retention of the Formulation 1 on the balloon catheter is not impacted by the lithotripsy treatment ( FIG. 8 ).
- Balloon catheters coated with Formulation 1 were tracked and placed at the site of inflation in porcine femoral arteries (female farm pigs, Sus scrofa domestica), without inflation, for 1 minute, and withdraw from the animal. Each animal was given ASA (0.081 g) and Clopidogrel (0.075 g) by mouth daily for three days prior to treatment, and was fasted overnight before the procedure. For surgical procedures, after sedation a marginal ear vein was cannulated for infusion of intravenous fluids and medications. The animal was intubated for administration of anesthetic gases and placed on the catheterization table. Under sterile conditions, a vascular introducer sheath was placed in the right carotid artery by surgical cut down.
- Nylon 12, Pebax, and Pebax with shockwave balloon catheter coated with Formulation 1 were tracked and placed at the site of inflation in porcine femoral arteries (female farm pigs, Sus scrofa domestica), and inflated to a balloon-to-artery diameter ratio of ⁇ 1.20.
- the nylon 12 and Pebax balloon were inflated and held at the treatment location of 1 minute for drug transfer, then withdrawn from the animal.
- the Pebax with shockwave balloon catheter were inflated, and a simulated lithotripsy treatment consisting of a 1 minute-long acoustic shock sequence were performed during the drug transfer period, then the balloon is withdrawn from the animal.
- ASA 0.081 g
- Clopidogrel 0.075 g
- the remaining coating on the balloon catheter after the procedure was extracted with appropriate solvent and PTX quanitified by RP-HPLC with benzonitrile as the internal standard.
- the % PTX remaining on the balloons was 56% for the Nylon 12 balloon, and 58% for the Pebax balloon; the corresponding value for the Pebax balloon used in simulated lithotripsy was 53%. These values are higher than those of Lutonix® and IN.PACTTM models, which were 22% and 16%, respectively (see FIG. 10 ). Further, the Shockwave lithotripsy treatment showed a minimal impact on drug retention on the device in a porcine model.
- Pebax with shockwave balloon catheter coated with Formulation 1 were tracked and placed at the site of inflation in porcine femoral arteries (female farm pigs, Sus scrofa domestica), and inflated to a balloon-to-artery diameter ratio of ⁇ 1.20.
- the Pebax with shockwave balloon catheter were inflated, and a simulated lithotripsy treatment consisting of a 1 minute-long acoustic shock sequence were performed during the drug transfer period.
- the PTA was deflated, tracked to a second location and inflated and a second 1 minute-long mock lithotripsy treatment was performed.
- the PTA was deflated and removed from the animal.
- ASA 0.081 g
- Clopidogrel 0.075 g
- the remaining coating on the balloon catheter after the procedure was extracted with appropriate solvent and PTX quantified by RP-HPLC with benzonitrile as the internal standard.
- the % PTX remaining on the balloons was for 53% the Pebax balloon post first lithotripsy treatment, and 24% post 2nd lithotripsy treatment (see FIG. 11 ). PTX retained on the balloon is available for further treatment.
- Coated Nylon 12 balloon catheter with Formulation 1 were inflated in porcine peripheral arteries similar to Example 21.
- Uncoated balloon (POBA) were used as controls and inflated in the similar fasion.
- POBA Uncoated balloon
- the animals were euthanized, the downstream skeletal muscles and main organs was excised and examined for any abnormalities, and the vasculature was perfused with lactated Ringer's solution, then neutral buffered formalin and processed for histology. Artery segments were embedded in paraffin, sectioned (approximately 5 ⁇ m) and stained with hematoxylin and eosin (H&E) and Movat stain.
- H&E hematoxylin and eosin
- a swine model was chosen for preclinical trials. Pigs were used because it had been extensively used for stent and angioplasty studies, resulting in a large volume of data on the vascular response properties and its correlation to human vascular response. These studies are conducted in vivo, as there are no suitable in vitro models that can mimic the complex biological responses to balloon angioplasty.
- porcine and human arteries have correlatively similar anatomy and the porcine model is recommended for use in preclinical studies by the FDA and Schwartz et al., Circulation. 106:1867-1873 (2002).
- Sus scrofa pigs were used in these studies.
- the animals were at least 10 weeks old, non-diseased, and all female or castrated.
- Each animal used in the study was attributed a study number and tagged by an ear tag at angioplasty.
- an ear tag was prepared but not installed. The protocol was reviewed and approved by the CIPAA for compliance with the Canadian Council on Animal Care regulations prior to study initiation.
- mice were administered oral acetylsalicylic acid (325 mg) and clopidogrel (300 mg initial dose, 75 mg subsequently) at least three days prior to intervention and continuing until sacrifice.
- the drugs were crushed to powder and mixed with food; therefore, treatment was not administered when animals were fasted.
- Anesthesia induction or tracheal intubation was achieved with propofol injected intravenously (IV) via a catheter in a vessel of the left or right ear.
- IV intravenously
- the subject animal was intubated and supported with mechanical ventilation. Isoflurane in oxygen was administered to maintain a surgical plane of anesthesia.
- mice were injected IM with long action penicillin (Duplocillin®, ProPen LA, Penpro or similar).
- Buprenophine HCl (Vetergesic) was administered IM was administered IM to prevent pain sensitization and minimize postoperative pain.
- the left or right femoral artery was accessed through an incision made in the inguinal region.
- An arterial sheath was introduced and advanced into the artery.
- Bupivacain 0.25% was infiltrated and/or locally dropped into the surgical site.
- An initial heparin bolus was administered and activated clotting time (ACT) was measured at least every 30 minutes and recorded. If ACT was ⁇ 300 seconds, additional heparin was administered.
- ACT activated clotting time
- Blood samples of at least 3 mL in each tube were obtained from all animals during the procedures (when the animal was under anesthesia) before treatment and prior to termination.
- For the blank at least 200 mL blood was collected and centrifuged to generate about 100 mL plasma. No blood samples was collected from the LIT animal. Samples were centrifuged as per Testing Facility SOP within approximately 1 hour of collection. Plasma was harvested and was kept on dry ice pending storage in a ⁇ 80° C. freezer pending shipment to the Analytical Chemistry Site. The blood sample harvested from the blank animal was performed after appropriate sedation after propofol administration.
- An initial angiography was performed prior to treatment. Under fluoroscopic guidance, a guide catheter was inserted through the sheath and advanced to the appropriate location. After placement of the guide catheter, nitroglycerin was delivered intraarterially to achieve arterial vasodilatation and angiographic images of the vessel were obtained with contrast media to identify the proper location for treatment site (designated pre-treatment angiography). A segment of artery was chosen, when possible, close to bifurcation or other markers, and measurements were performed up to the ostium to facilitate the site location at harvest. A guidewire was inserted into the chosen artery. Quantitative Vessel Angiography (QVA) was performed at this time to document the reference diameter for balloon angioplasty. Proximal and distal reference diameter was noted.
- QVA Quantitative Vessel Angiography
- a final angiography was also performed after treatment. After induction of anesthesia, the artery of interest was accessed through an incision made in the inguinal region or a percutaneous access was used for some animals. Nitroglycerin was delivered to the treated arteries to achieve vasodilatation and QCA image capture was performed for each treated site using fluoroscopy. Each treated artery was qualitatively evaluated for lumen narrowing (treated and proximal/distal non-treated segments), dissection, thrombosis, and aneurysm.
- the fluoroscopic output from the treated site (pre-treatment, balloon and post-treatment angiography) and at explantation (final angiography) were recorded in digital format.
- a single image was selected of the treated area; from this image, QVA measurements were obtained using Medis QCA-CMS 6.0 or QAngio® XA 7.3 (or higher) system. Parameters measured or calculated included:
- necropsy defined as gross examination of the heart and treated vessels, the whole body (external surface), all orifices, thoracic and abdominal cavities, and their contents. Lesions found during necropsy procedures/tissue collection were documented and collected when feasible, immersion-fixed in neutral buffered formalin (NBF) and processed for histology. Untreated sites proximal and distal to the treated site, as well as the myocardium downstream to the treated site, were also harvested for analysis. All treated sites were used for pharmacokinetic analysis.
- Hearts were perfused with lactated Ringer's solution (LRS), then NBF and immersed in NBF with the animal's ear tag until processed for histology.
- the blank animal was used as a control for blood and tissue analysis.
- LAD, LCx, and RCA vessels were harvested.
- Hearts were opened and then immersed in NBF with the animal's ear tag until possible processing for histology.
- Portions of the distal myocardium from the blank animal were also harvested from the LAD, LCx, and RCA. A gross examination of this animal was performed in order to assess any genetic abnormalities, such as cysts, that may have been present in the trial animals.
- the objective of the study was to determine the amount of drug delivered from the drug-coated balloons (DCBs) and retained after 28 days in the arterial wall and surrounding tissue of porince (Sus scrofa) coronary arteries.
- DCBs drug-coated balloons
- the three test articles were paclitaxel-containing drug-coated balloon formulations with Formulation 1, Formulation 3, and Formulation 4.
- uncoated balloons or Biotronik® Pantera Lux were used. 3.0 mm ⁇ 20.0 mm balloons were used.
- treatments were performed in the three main coronary arteries: left anterior descending coronary artery (LAD), left circumflex coronary artery (LCx), and right coronary artery (RCA).
- LAD left anterior descending coronary artery
- LCx left circumflex coronary artery
- RCA right coronary artery
- Formulation 1-coated PTA balloons were used in this experiment: Formulation 1-coated percutaneous transluminal coronary angioplasty (PTCA), compared to Biotronik® Pantera Lux, and Formulation 1-coated percutaneous transluminal angioplasty (PTA) compared to Medtronic® IN.PACTTM.
- PTCA percutaneous transluminal coronary angioplasty
- PTA percutaneous transluminal angioplasty
- Treatments were performed either in the peripheral or coronary arteries.
- PTCA treatment was performed in the three main coronary arteries: left anterior descending coronary artery (LAD), left circumflex coronary artery (LCx), and right coronary artery (RCA).
- LAD left anterior descending coronary artery
- LCx left circumflex coronary artery
- RCA right coronary artery
- SFAs superficial femoral arteries
- PFAs profunda femoris arteries
- Formulation 1-treated peripheral arteries show lower PTX retention than those treated with the IN.PACTTM control
- the drug tissue level for Formulation 1-treated arteries at 7 days is within the range of clinically proven devices such as Lutonix (Bard) (1.0 ⁇ 0.9 ⁇ g/g 7 d after treatment with Lutonix balloons) (Yazdani et al., Catheterization and Cardiovascular Interventions. 83:132-140 (2014)).
- Lutonix Board
- This pilot study was conducted with minimal coating optimization pre-work.
- analysis supports the potential for increased PTX uptake/retention for Formulation 1-coated balloons (near the level of In.Pact) by optimizing the coating morphology to provide full balloon surface coverage.
- Formulation 1-treated coronary arteries show PTX tissue concentrations of about 104 ⁇ g/g, a high value that is consistent with the 38 ⁇ g/g concentration observed at 28 days in the previous study described in study K12.
- Formulation 5 and Formulation 8 coated Nylon 12 coupon were immersed into phosphate buffered saline solution for 2 minutes. Formulation 5 remained intact, while Formulation 8 exhibited significant particle shedding.
- sirolimus crystalline, purchased from LC Laboratories®
- LC Laboratories® crystalline, purchased from LC Laboratories®
- CryoMill Retsch®
- T m 180° C.
- Cyro-milled sirolimus from Example 29 was suspended in methyl tert-butyl ether (MTBE) with dissolved Compound 1 (range from 50:50 to 95:5 w/w) with varying sirolimus concentration (20-120 mg/mL) and used while stirring. Suspensions were drop casted onto Nylon 12 coupons and visually inspected. It was noted that the higher the sirolimus concentration, the more crystalline the coating.
- MTBE methyl tert-butyl ether
- Formulation 9 closer inspection of Formulation 9 coatings under SEM indicates that sirolimus concentrations greater than 80 mg/mL are substantially crystalline, as no clear evidence of amorphous morphological features was found during imaging. Formulation 9, therefore, yields coatings of varying degrees of sirolimus crystallinity depending on concentration. Specifically, solutions of a concentration 80 mg/mL can be used to prepare highly crystalline reference samples of Formulation 9 (crystalline control). % crystallinity of the crystalline control as measured by PXRD: 92%.
- Formulation 10 in THF was coated onto 3.0 ⁇ 20 mm Nylon 12 percutaneous transluminal coronary angioplasty (PTCA) balloon catheters and 5.0 ⁇ 60 mm Nylon 12 percutaneous transluminal angioplasty (PTA) balloon catheters by a drop-and-drag coating method and dried overnight to form coatings containing varying sirolimus loading (3.0-7.0 ⁇ g/mm 2 ).
- PTCA percutaneous transluminal coronary angioplasty
- PTA percutaneous transluminal angioplasty
- Formulation 9 was coated onto 3.0 ⁇ 20 mm Nylon 12 percutaneous transluminal coronary angioplasty (PTCA) balloon catheters and 5.0 ⁇ 60 mm Nylon 12 percutaneous transluminal angioplasty (PTA) balloon catheters by a drop-and-drag coating method and dried overnight to form coatings containing varying sirolimus loading (3.0-7.0 ⁇ g/mm 2 ). SEM images of all coated balloons displayed the expected crystalline drug morphology (see FIG. 15 ).
- PTCA balloon catheters were coated with Formulation 9 as in Example 32 and subjected to various drying processes immediately after coating: Process 1: room temperature overnight; Process 2: heat (50° C.) for 1 to 5 days; Process 3: heat (50° C.) and vacuum for 1 to 5 days. All coated balloons were then sterilized by EtO. SEM images of all coated balloons displayed the expected crystalline drug morphology. Process 2 and Process 3 balloon coatings showed fewer morphological changes post-sterilization suggesting bulk removal of solvent ( FIG. 16 ).
- Residual MTBE solvent Process 1 pre-sterilization 59120 ppm, post-sterilization 12810 ppm; Process 2 pre-sterilization 7910 ppm, post-sterilization 2011 ppm; Process 3 pre-sterilization 2104 ppm, post-sterilization 400 ppm.
- Formulation 9 Formulation 10 (amorphous control), and a suspension of Compound 1 with 80 mg/mL sirolimus (crystalline control, as described in Example 30) were drop-casted onto Nylon 12 coupons and dried as in Example 33.
- Nylon 12 coupons were immersed in 40 mL of PBS tween buffer and placed in a shaker at 37° C. for 24 hours. Buffer exchanges were performed at 1 hour and 2 hours to remove loose particles.
- PBS tween was removed from the container, and the concentration of sirolimus release in PBS tween buffer was directly quantified using RP-HPLC ( FIG. 17 ). The remaining sirolimus on coupon was measured by dissolving the coating in acetonitrile and quantified using RP-HPLC.
- PTCA balloon catheters were coated and dried in a similar fashion as Example 34. After EtO sterilization, balloons were immersed in 40 mL of PBS tween buffer and placed in a shaker at 37° C. for 24 hours. Buffer exchanges were performed at 1 hour and 2 hours to remove loose particles. At 24 hours, PBS tween was removed from the container, and the concentration of sirolimus release in PBS tween buffer was directly quantified using RP-HPLC. The remaining sirolimus on PTCA balloon catheters was measured by dissolving the coating in acetonitrile and quantified using RP-HPLC.
- Corresponding sirolimus-only control samples were prepared at the same concentrations and in the same solvent systems as Formulation 7 and Formulation 9 by drop-casting onto Nylon 12 coupons, and then sterilized by EtO. Under sterile conditions, the Nylon 12 coupons were immersed in Dulbecco's Modified Eagle Medium (DMEM) and placed in a shaker at 37° C. for 5 hours towards a target concentration >20 ng/mL of released sirolimus.
- DMEM Dulbecco's Modified Eagle Medium
- DMEM Concentrations in DMEM were directly quantified using RP-HPLC, then adjusted to 20 ng/mL by dilution with DMEM and Fetal Bovine Serum (FBS, 10% overall content).
- RASMCs Rat Aortic Smooth Muscle Cells
- the growth media was removed by aspiration and exchanged with the drug release samples described above, each adjusted to 20 ng/mL. Metabolic activity was then measured after a growth period of 72 hours using an analytical wavelength of 450 nm, and a reference wavelength of 650 nm. Data were normalized against RASMCs grown in drug-free media, and compared against cell culture media spiked with sirolimus at 20 ng/mL, prepared as described above.
- a suitable apparatus was used based on the principle of light-obscuration that allows for an automatic determination of the size of particles and the number of particles according to size.
- An environmental check was performed as per USP ⁇ 788> to confirm suitability of the testing environment.
- the apparatus is calibrated using dispersions of spherical particles for known sizes between 10 mm to 150 mm. These standard particles were dispersed in particle-free water. Care was taken to avoid aggregation of particles during dispersion.
- USP41-NF36 S1 ⁇ 788> was used as a guideline for sample testing.
- Phosphate buffered saline at 37° C. was filled through silicone tubing connections.
- a Nylon 12 PTCA balloon catheter coated with Formulation 9+Process 1 was tracked through the silicone tubing, then inflated to establish contact with silicone tubing. Once inflated, the balloon was held in place for 1 minute, and then deflated and removed from the tubing. Buffer after inflation was analyzed by a HIAC Liquid Particle Counter (MII B1616712). Noted that uncoated PTCA balloon catheters were used as control samples.
- Phosphate buffered saline at 37° C. was pumped through silicone tubing connections.
- the pump flow rate was set similar to the rate of blood flow through femoral arteries (350 mL/min).
- a Nylon 12 PTA balloon catheter coated with Formulation 9+Process 2 was placed in the middle of the buffer flow for 2 minutes.
- the sirolimus remaining on the balloon catheter was measured by dissolving the coating in acetonitrile and quantified using RP-HPLC. The % sirolimus remaining was observed to be 89% for PTA containing 3.0 ⁇ g/mm 2 sirolimus and 82% for PTA containing 6.0 ⁇ g/mm 2 sirolimus.
- Sirolimus retention for Formulation 9 was higher than drug retention of PTX competitor benchmarks: Ranger, 99%, Lutonix, 52%, Stellarex, 71%, and In.Pact, 62% (see FIG. 18 ).
- the high retention of sirolimus observed for Formulation 9 was similar to the high retention of PTX observed for Formulation 1, 93% for Nylon 12 PTA balloon catheter coated with Formulation 1 and 85% for Pebax PTA lithotripsy catheter coated with Formulation 1 (see FIG. 18 ). This would suggest that a high percentarge of the sirolimus payload would be available at the target site and not reduced by transit-associated loss.
- Phosphate buffered saline at 37° C. was pumped through silicone tubing connections.
- the pump flow rate was set similar to the rate of blood flow through femoral arteries (350 mL/min).
- a Nylon 12 PTCA balloon catheter coated with Formulation 9+Process 1 and Formulation 9+Process 2 was tracked through the silicone tubing under flow, then inflated to establish contact with silicone tubing. Once inflated, the balloon was held in place for 1 minute, and then deflated and removed from the tubing. The siroliums remaining on the balloon catheter was measured by stripping the coating and quantified using RP-HPLC.
- % sirolimus remaining on balloons PTCA 3.0 ⁇ g/mm 2 12%, PTCA 6.0 ⁇ g/mm 2 10%, PTA 3.0 ⁇ g/mm 2 30%, PTA 6.0 ⁇ g/mm 2 19%, Concept Medical MagicTouch PTCA 20%.
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US16/797,189 US11318232B2 (en) | 2018-05-22 | 2020-02-21 | Compositions and methods for delivering drugs to a vessel wall |
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Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020256898A1 (fr) | 2019-06-19 | 2020-12-24 | Boston Scientific Scimed, Inc. | Génération d'ondes de pression photoacoustiques depuis une surface de ballonnet pour réduire des lésions vasculaires |
US11717139B2 (en) | 2019-06-19 | 2023-08-08 | Bolt Medical, Inc. | Plasma creation via nonaqueous optical breakdown of laser pulse energy for breakup of vascular calcium |
US11660427B2 (en) | 2019-06-24 | 2023-05-30 | Boston Scientific Scimed, Inc. | Superheating system for inertial impulse generation to disrupt vascular lesions |
US20200406009A1 (en) | 2019-06-26 | 2020-12-31 | Boston Scientific Scimed, Inc. | Focusing element for plasma system to disrupt vascular lesions |
US11672599B2 (en) * | 2020-03-09 | 2023-06-13 | Bolt Medical, Inc. | Acoustic performance monitoring system and method within intravascular lithotripsy device |
US20210290286A1 (en) | 2020-03-18 | 2021-09-23 | Bolt Medical, Inc. | Optical analyzer assembly and method for intravascular lithotripsy device |
US11707323B2 (en) | 2020-04-03 | 2023-07-25 | Bolt Medical, Inc. | Electrical analyzer assembly for intravascular lithotripsy device |
US12016610B2 (en) | 2020-12-11 | 2024-06-25 | Bolt Medical, Inc. | Catheter system for valvuloplasty procedure |
US11672585B2 (en) | 2021-01-12 | 2023-06-13 | Bolt Medical, Inc. | Balloon assembly for valvuloplasty catheter system |
US11648057B2 (en) | 2021-05-10 | 2023-05-16 | Bolt Medical, Inc. | Optical analyzer assembly with safety shutdown system for intravascular lithotripsy device |
US11806075B2 (en) | 2021-06-07 | 2023-11-07 | Bolt Medical, Inc. | Active alignment system and method for laser optical coupling |
US11839391B2 (en) | 2021-12-14 | 2023-12-12 | Bolt Medical, Inc. | Optical emitter housing assembly for intravascular lithotripsy device |
CN115253030A (zh) * | 2022-06-01 | 2022-11-01 | 惠州市顺美医疗科技有限公司 | 一种球囊扩张导管及其生物涂层的涂覆方法 |
Citations (73)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3929922A (en) | 1965-09-29 | 1975-12-30 | Studiengesellschaft Kohle Mbh | Novel large ring compounds |
US5362718A (en) | 1994-04-18 | 1994-11-08 | American Home Products Corporation | Rapamycin hydroxyesters |
US5665772A (en) | 1992-10-09 | 1997-09-09 | Sandoz Ltd. | O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants |
US5868719A (en) | 1997-01-15 | 1999-02-09 | Boston Scientific Corporation | Drug delivery balloon catheter device |
US5954706A (en) | 1990-12-28 | 1999-09-21 | Boston Scientific Corporation | Drug delivery |
US6127507A (en) | 1995-08-03 | 2000-10-03 | Santerre; Paul J. | Fluoroligomer surface modifiers for polymers and articles made therefrom |
US6280411B1 (en) | 1998-05-18 | 2001-08-28 | Scimed Life Systems, Inc. | Localized delivery of drug agents |
EP1087801B1 (fr) | 1998-06-26 | 2002-01-16 | Quanam Medical Corporation | Inhibiteurs de topoisomerase permettant de prevenir la restenose |
WO2002098477A2 (fr) | 2001-06-07 | 2002-12-12 | Santerre Paul J | Modificateurs de surfaces bioactifs destines a des polymeres et a des articles fabriques a partir de polymeres |
CA2470524A1 (fr) | 2001-12-21 | 2003-07-24 | David S. Soane | Utilisation d'oligomeres et de polymeres pour solubiliser, stabiliser et distribuer un medicament |
US20030204238A1 (en) | 2002-04-26 | 2003-10-30 | Eugene Tedeschi | Coated stent with crimpable coating |
CA2484269A1 (fr) | 2002-05-09 | 2003-11-20 | Hemoteq Gmbh | Composes et procedes pour recouvrir de facon hemocompatible des surfaces |
WO2004028610A2 (fr) | 2002-09-20 | 2004-04-08 | Bavaria Medizin Technologie Gmbh | Dispositif medical pour l'administration de medicaments |
EP0975340B1 (fr) | 1997-03-31 | 2004-10-06 | Boston Scientific Limited | Inhibiteur therapeutique des cellules des muscles lisses de la paroi vasculaire |
US6890546B2 (en) | 1998-09-24 | 2005-05-10 | Abbott Laboratories | Medical devices containing rapamycin analogs |
US20050131527A1 (en) | 2003-12-12 | 2005-06-16 | Pathak Chandrashekhar P. | Implantable medical devices with fluorinated polymer coatings, and methods of coating thereof |
US6939320B2 (en) | 1998-05-18 | 2005-09-06 | Boston Scientific Scimed., Inc. | Localized delivery of drug agents |
CA2555364A1 (fr) | 2004-03-10 | 2005-09-22 | Orbus Medical Technologies, Inc. | Capture de cellules endotheliales progenitrices au moyen d'un dispositif medical implantable a elution medicamenteuse |
US20060229711A1 (en) | 2005-04-05 | 2006-10-12 | Elixir Medical Corporation | Degradable implantable medical devices |
WO2007004067A2 (fr) | 2005-04-15 | 2007-01-11 | Interface Biologics Inc. | Procedes et compositions permettant d'administrer des agents biologiquement actifs |
WO2007040557A1 (fr) | 2005-09-21 | 2007-04-12 | Surmodics, Inc. | Revetements et articles a polysaccharides naturels biodegradables |
US7226473B2 (en) | 2003-05-23 | 2007-06-05 | Brar Balbir S | Treatment of stenotic regions |
EP1666071B1 (fr) | 2001-03-26 | 2007-08-15 | Bayer Schering Pharma Aktiengesellschaft | Préparation de prévention de la restenose |
US20070190103A1 (en) | 2006-02-10 | 2007-08-16 | Hossainy Syed F A | Implantable medical device with surface-eroding polyester drug delivery coating |
EP1339440B1 (fr) | 2000-07-13 | 2007-12-05 | Boston Scientific Limited | Dispositif d'administration d'agent therapeutique implantable ou inserable |
WO2007148230A2 (fr) | 2006-04-14 | 2007-12-27 | Interface Biologics Incorporated | Polymères greffés et leurs utilisations |
US20080021385A1 (en) | 1997-08-13 | 2008-01-24 | Scimed Life Systems, Inc. | Loading and release of water-insoluble drugs |
WO2008076345A1 (fr) | 2006-12-14 | 2008-06-26 | Interface Biologics Inc. | Macromolécules modificatrices de surface à fortes températures de dégradation et leur utilisation |
CA2673991A1 (fr) | 2007-01-21 | 2008-07-24 | Hemoteq Ag | Procedes d'enrobage de ballonnets de catheters avec une quantite definie d'un agent actif |
US20080279911A1 (en) | 2007-05-11 | 2008-11-13 | Boston Scientific Scimed, Inc. | Medical devices having crosslinked polymeric surfaces |
US20090076595A1 (en) | 2007-09-14 | 2009-03-19 | Boston Scientific Scimed, Inc. | Medical devices having bioerodable layers for the release of therapeutic agents |
WO2009043174A1 (fr) | 2007-10-05 | 2009-04-09 | Interface Biologics Inc. | Polymères réticulés oligofluorés et leurs utilisations |
WO2009049426A1 (fr) | 2007-10-19 | 2009-04-23 | Interface Biologics Inc. | Revêtements autodégradables |
US7572245B2 (en) | 2003-09-15 | 2009-08-11 | Atrium Medical Corporation | Application of a therapeutic substance to a tissue location using an expandable medical device |
WO2009129385A1 (fr) | 2008-04-16 | 2009-10-22 | Abbott Laboratories | Lipides cationiques et utilisations de ceux-ci |
US7655038B2 (en) | 2003-02-28 | 2010-02-02 | Biointeractions Ltd. | Polymeric network system for medical devices and methods of use |
EP1582210B1 (fr) | 1996-12-02 | 2010-02-10 | Angiotech International AG | Utilisation d'un agent antimicrotubulaire pour le traitement et la prévention des adhérences chirurgicales |
WO2010025398A1 (fr) | 2008-08-28 | 2010-03-04 | Interface Biologics Inc. | Biuret thermiquement stable et macromolécules à base d’isocyanurate modificatrices de surface et leurs utilisations |
US7811622B2 (en) | 1995-06-07 | 2010-10-12 | Cook Incorporated | Coated implantable medical device |
US20100272774A1 (en) | 2009-04-28 | 2010-10-28 | Surmodics, Inc. | Devices and methods for delivery of bioactive agents |
US20100286608A1 (en) | 2009-05-07 | 2010-11-11 | Biotronik Vi Patent Ag | Drug-coated balloon catheter and method for the production thereof |
US20110015725A1 (en) | 2002-07-12 | 2011-01-20 | Bates Brian L | Coated medical device |
WO2010111232A9 (fr) | 2009-03-23 | 2011-03-03 | Micell Technologies, Inc. | Dispositif médical d'administration de médicament |
EP2301619A1 (fr) | 2004-03-19 | 2011-03-30 | Abbott Laboratories | Administration de médicaments multiples à partir d'un ballonnet et d'une prothèse |
WO2011072398A1 (fr) | 2009-12-18 | 2011-06-23 | Interface Biologics, Inc. | Administration locale de médicaments à partir de revêtements auto-assemblés |
CA2793832A1 (fr) | 2010-03-25 | 2011-09-29 | Lixiao Wang | Revetements liberant un medicament pour dispositifs medicaux |
EP2386322A2 (fr) | 2006-07-03 | 2011-11-16 | Hemoteq AG | Fabrication, procédé et utilisation de produits médicaux libérant un agent actif pour le maintien ouvert permanent de vaisseaux sanguins |
WO2011147408A2 (fr) | 2010-05-27 | 2011-12-01 | Hemoteq Ag | Produit médical revêtu d'une couche non particulaire de libération de principe actif |
US20110295200A1 (en) | 2009-01-09 | 2011-12-01 | Ulrich Speck | Drug-eluting medical device |
EP1632259B1 (fr) | 1993-07-19 | 2011-12-21 | Angiotech Pharmaceuticals, Inc. | Compositions anti-angiogéniques et leurs procédés d'utilisation |
US8177743B2 (en) | 1998-05-18 | 2012-05-15 | Boston Scientific Scimed, Inc. | Localized delivery of drug agents |
US20120165786A1 (en) | 2010-06-30 | 2012-06-28 | Chappa Ralph A | Lipid coating for medical devices delivering bioactive agent |
US20120296274A1 (en) | 2011-05-20 | 2012-11-22 | Surmodics, Inc. | Delivery of coated hydrophobic active agent particles |
US20130013048A1 (en) | 2004-03-19 | 2013-01-10 | Abbott Laboratories | Multiple drug delivery from a balloon and a prosthesis |
US8425459B2 (en) | 2006-11-20 | 2013-04-23 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent |
US20130190689A1 (en) | 2011-05-20 | 2013-07-25 | Surmodics, Inc. | Delivery of coated hydrophobic active agent particles |
EP2636416A2 (fr) | 2006-07-07 | 2013-09-11 | Abbott Cardiovascular Systems Inc. | Revêtements à base de copolymère séquencé à séparation de phase pour des dispositifs médicaux implantables |
US20140004253A1 (en) | 2012-06-28 | 2014-01-02 | Covidien Lp | Post-processing of a medical device to control morphology and mechanical properties |
US20140207061A1 (en) | 2006-11-14 | 2014-07-24 | Boston Scientific Scimed, Inc. | Medical Devices and Related Methods |
US20140288497A1 (en) | 2008-05-01 | 2014-09-25 | Bayer Pharma Aktiengesellschaft | Catheter Balloon Drug Adherence Techniques and Methods |
EP2019698B1 (fr) | 2006-05-18 | 2014-11-12 | Boston Scientific Limited | Dispositifs médicaux comprenant des zones polymériques à base de copolymère blocs d'éther vinylique |
US20140350522A1 (en) | 2011-07-15 | 2014-11-27 | Micell Technologies, Inc. | Drug delivery medical device |
US20150045877A1 (en) | 2006-12-15 | 2015-02-12 | Abbott Cardiovascular Systems Inc. | Regional delivery of therapeutic agents for the treatment of vascular diseases |
WO2015070814A1 (fr) | 2013-11-15 | 2015-05-21 | 微创心脉医疗科技(上海)有限公司 | Ballonnet à élution médicamenteuse et procédé de fabrication |
US20150140107A1 (en) | 2011-05-20 | 2015-05-21 | Surmodics, Inc. | Delivery of hydrophobic active agent particles |
US20150190519A1 (en) | 1997-06-27 | 2015-07-09 | Abraxis Bioscience, Llc | Compositions and methods for treatment of hyperplasia |
US20150196690A1 (en) | 2009-12-11 | 2015-07-16 | Abbott Cardiovascular Systems Inc. | Coatings with tunable molecular architecture for drug-coated balloon |
US20150209334A1 (en) | 2001-01-16 | 2015-07-30 | Vascular Therapies | Apparatus and methods for preventing or treating failure of hemodialysis vascular access and other vascular grafts |
US20150209555A1 (en) | 2014-01-24 | 2015-07-30 | Covidien Lp | Coatings for medical devices |
US20150209482A1 (en) | 2004-09-28 | 2015-07-30 | Atrium Medical Corporation | Cross-linked fatty acid-based biomaterials |
US20150231308A1 (en) | 2012-07-10 | 2015-08-20 | Bayer Pharma Aktiengesellschaft | Catheter with drug coating |
US20150250926A1 (en) | 2011-10-18 | 2015-09-10 | Micell Technologies, Inc. | Drug delivery medical device |
US9206283B1 (en) | 2013-03-15 | 2015-12-08 | Angiodynamics, Inc. | Thermoplastic polyurethane admixtures |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120263778A1 (en) * | 2009-12-16 | 2012-10-18 | Bayer Intellectual Property Gmbh | Polyurethane urea for stent coatings |
US20140371717A1 (en) * | 2011-10-18 | 2014-12-18 | Micell Technologies, Inc. | Drug delivery medical device |
CN105377319B (zh) * | 2013-03-15 | 2022-01-28 | 波纹疗法公司 | 用于药物释放的化合物和组合物 |
-
2019
- 2019-05-22 WO PCT/CA2019/050694 patent/WO2019222843A1/fr unknown
- 2019-05-22 JP JP2020565270A patent/JP2021531061A/ja active Pending
- 2019-05-22 EP EP19807198.7A patent/EP3796948A4/fr not_active Withdrawn
- 2019-05-22 CN CN201980048189.2A patent/CN112638436A/zh active Pending
-
2020
- 2020-02-21 US US16/797,189 patent/US11318232B2/en active Active
-
2022
- 2022-04-13 US US17/719,529 patent/US20220362440A1/en active Pending
Patent Citations (111)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3929922A (en) | 1965-09-29 | 1975-12-30 | Studiengesellschaft Kohle Mbh | Novel large ring compounds |
US5954706A (en) | 1990-12-28 | 1999-09-21 | Boston Scientific Corporation | Drug delivery |
US5665772A (en) | 1992-10-09 | 1997-09-09 | Sandoz Ltd. | O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants |
EP1632259B1 (fr) | 1993-07-19 | 2011-12-21 | Angiotech Pharmaceuticals, Inc. | Compositions anti-angiogéniques et leurs procédés d'utilisation |
US5362718A (en) | 1994-04-18 | 1994-11-08 | American Home Products Corporation | Rapamycin hydroxyesters |
US7811622B2 (en) | 1995-06-07 | 2010-10-12 | Cook Incorporated | Coated implantable medical device |
US6127507A (en) | 1995-08-03 | 2000-10-03 | Santerre; Paul J. | Fluoroligomer surface modifiers for polymers and articles made therefrom |
EP1582210B1 (fr) | 1996-12-02 | 2010-02-10 | Angiotech International AG | Utilisation d'un agent antimicrotubulaire pour le traitement et la prévention des adhérences chirurgicales |
US5868719A (en) | 1997-01-15 | 1999-02-09 | Boston Scientific Corporation | Drug delivery balloon catheter device |
EP0975340B1 (fr) | 1997-03-31 | 2004-10-06 | Boston Scientific Limited | Inhibiteur therapeutique des cellules des muscles lisses de la paroi vasculaire |
EP2292225B1 (fr) | 1997-03-31 | 2012-05-09 | Boston Scientific Scimed Limited | Forme de dosage comprénant du taxol en forme cristalline |
US20150190519A1 (en) | 1997-06-27 | 2015-07-09 | Abraxis Bioscience, Llc | Compositions and methods for treatment of hyperplasia |
US20080021385A1 (en) | 1997-08-13 | 2008-01-24 | Scimed Life Systems, Inc. | Loading and release of water-insoluble drugs |
US20120239001A1 (en) | 1997-08-13 | 2012-09-20 | Boston Scientific Scimed, Inc. | Loading and release of water-insoluble drugs |
US8177743B2 (en) | 1998-05-18 | 2012-05-15 | Boston Scientific Scimed, Inc. | Localized delivery of drug agents |
US6939320B2 (en) | 1998-05-18 | 2005-09-06 | Boston Scientific Scimed., Inc. | Localized delivery of drug agents |
US6280411B1 (en) | 1998-05-18 | 2001-08-28 | Scimed Life Systems, Inc. | Localized delivery of drug agents |
EP1087801B1 (fr) | 1998-06-26 | 2002-01-16 | Quanam Medical Corporation | Inhibiteurs de topoisomerase permettant de prevenir la restenose |
US6890546B2 (en) | 1998-09-24 | 2005-05-10 | Abbott Laboratories | Medical devices containing rapamycin analogs |
EP1339440B1 (fr) | 2000-07-13 | 2007-12-05 | Boston Scientific Limited | Dispositif d'administration d'agent therapeutique implantable ou inserable |
US20140005541A1 (en) | 2000-10-31 | 2014-01-02 | Cook Medical Technolgies Llc | Coated medical device |
US8673387B2 (en) | 2000-10-31 | 2014-03-18 | Cook Medical Technologies Llc | Coated medical device |
US20140178563A1 (en) | 2000-10-31 | 2014-06-26 | Cook Medical Technologies Llc | Coated medical device |
US8172793B2 (en) | 2000-10-31 | 2012-05-08 | Cook Medical Technologies Llc | Coated medical device |
US20150209334A1 (en) | 2001-01-16 | 2015-07-30 | Vascular Therapies | Apparatus and methods for preventing or treating failure of hemodialysis vascular access and other vascular grafts |
EP1666071B1 (fr) | 2001-03-26 | 2007-08-15 | Bayer Schering Pharma Aktiengesellschaft | Préparation de prévention de la restenose |
EP1666070B1 (fr) | 2001-03-26 | 2007-09-05 | Bayer Schering Pharma Aktiengesellschaft | Preparation de prevention de la restenose |
WO2002098477A2 (fr) | 2001-06-07 | 2002-12-12 | Santerre Paul J | Modificateurs de surfaces bioactifs destines a des polymeres et a des articles fabriques a partir de polymeres |
US6770725B2 (en) | 2001-06-07 | 2004-08-03 | Paul J. Santerre | Bioactive surface modifiers for polymers and articles made therefrom |
US20030097120A1 (en) | 2001-06-07 | 2003-05-22 | Santerre Paul J. | Bioactive surface modifiers for polymers and articles made therefrom |
EP2258415B1 (fr) | 2001-09-10 | 2014-10-15 | Abbott Laboratories | Dispositifs medicaux contenant des analogues de la rapamycine |
CA2470524A1 (fr) | 2001-12-21 | 2003-07-24 | David S. Soane | Utilisation d'oligomeres et de polymeres pour solubiliser, stabiliser et distribuer un medicament |
US20030204238A1 (en) | 2002-04-26 | 2003-10-30 | Eugene Tedeschi | Coated stent with crimpable coating |
CA2484269A1 (fr) | 2002-05-09 | 2003-11-20 | Hemoteq Gmbh | Composes et procedes pour recouvrir de facon hemocompatible des surfaces |
USRE45500E1 (en) | 2002-06-25 | 2015-04-28 | Biointeractions Ltd. | Polymeric network system for medical devices and methods of use |
EP2324867B1 (fr) | 2002-07-12 | 2014-06-18 | Cook Medical Technologies LLC | Ballons d'angioplastie revêtis d'agents pharmaceutiques en forme expansée |
EP2324866B1 (fr) | 2002-07-12 | 2014-06-18 | Cook Medical Technologies LLC | Ballons d'angioplastie revêtis d'agents pharmaceutiques en forme expansée |
US20110015725A1 (en) | 2002-07-12 | 2011-01-20 | Bates Brian L | Coated medical device |
EP2857049A1 (fr) | 2002-09-20 | 2015-04-08 | Bayer Intellectual Property GmbH | Dispositif médical d'administration de médicament |
US20140228751A1 (en) | 2002-09-20 | 2014-08-14 | Bayer Intellectual Property Gmbh | Medical Device for Dispersing Medicaments |
WO2004028610A2 (fr) | 2002-09-20 | 2004-04-08 | Bavaria Medizin Technologie Gmbh | Dispositif medical pour l'administration de medicaments |
EP2857048A1 (fr) | 2002-09-20 | 2015-04-08 | Bayer Intellectual Property GmbH | Dispositif médical d'administration de médicament |
US20060020243A1 (en) | 2002-09-20 | 2006-01-26 | Ulrich Speck | Medical device for dispensing medicaments |
EP1539266B1 (fr) | 2002-09-20 | 2008-04-09 | Bayer Schering Pharma Aktiengesellschaft | Dispositif medical destine a la distribution d'un medicament |
US8439868B2 (en) | 2002-09-20 | 2013-05-14 | Bayer Pharma AG | Medical device for dispersing medicaments |
EP2216055A1 (fr) | 2002-09-20 | 2010-08-11 | Bayer Schering Pharma AG | Dispositif medical pour l'administration de medicaments |
EP2216056A1 (fr) | 2002-09-20 | 2010-08-11 | Bayer Schering Pharma AG | dispositif medical pour l'administration de medicaments |
US8257305B2 (en) | 2002-09-20 | 2012-09-04 | Bayer Pharma Aktiengesellschaft | Medical device for dispensing medicaments |
EP1857127A1 (fr) | 2002-09-20 | 2007-11-21 | Bayer Schering Pharma Aktiengesellschaft | Cathéter à ballonnet pour la délivrance de Paclitaxel |
US7655038B2 (en) | 2003-02-28 | 2010-02-02 | Biointeractions Ltd. | Polymeric network system for medical devices and methods of use |
US7226473B2 (en) | 2003-05-23 | 2007-06-05 | Brar Balbir S | Treatment of stenotic regions |
US7572245B2 (en) | 2003-09-15 | 2009-08-11 | Atrium Medical Corporation | Application of a therapeutic substance to a tissue location using an expandable medical device |
US20050131527A1 (en) | 2003-12-12 | 2005-06-16 | Pathak Chandrashekhar P. | Implantable medical devices with fluorinated polymer coatings, and methods of coating thereof |
CA2555364A1 (fr) | 2004-03-10 | 2005-09-22 | Orbus Medical Technologies, Inc. | Capture de cellules endotheliales progenitrices au moyen d'un dispositif medical implantable a elution medicamenteuse |
EP2301619A1 (fr) | 2004-03-19 | 2011-03-30 | Abbott Laboratories | Administration de médicaments multiples à partir d'un ballonnet et d'une prothèse |
US20130013048A1 (en) | 2004-03-19 | 2013-01-10 | Abbott Laboratories | Multiple drug delivery from a balloon and a prosthesis |
US20150196692A1 (en) | 2004-03-19 | 2015-07-16 | Abbott Laboratories | Multiple drug delivery from a balloon and a prosthesis |
US20150209482A1 (en) | 2004-09-28 | 2015-07-30 | Atrium Medical Corporation | Cross-linked fatty acid-based biomaterials |
US20060229711A1 (en) | 2005-04-05 | 2006-10-12 | Elixir Medical Corporation | Degradable implantable medical devices |
WO2007004067A2 (fr) | 2005-04-15 | 2007-01-11 | Interface Biologics Inc. | Procedes et compositions permettant d'administrer des agents biologiquement actifs |
US20070037891A1 (en) | 2005-04-15 | 2007-02-15 | Roseita Esfand | Methods and compositions for the delivery of biologically active agents |
WO2007040557A1 (fr) | 2005-09-21 | 2007-04-12 | Surmodics, Inc. | Revetements et articles a polysaccharides naturels biodegradables |
US20070190103A1 (en) | 2006-02-10 | 2007-08-16 | Hossainy Syed F A | Implantable medical device with surface-eroding polyester drug delivery coating |
JP2009533519A (ja) | 2006-04-14 | 2009-09-17 | インターフェース バイオロジクス,インコーポレーテッド | グラフトポリマーおよびその使用 |
WO2007148230A2 (fr) | 2006-04-14 | 2007-12-27 | Interface Biologics Incorporated | Polymères greffés et leurs utilisations |
EP2019698B1 (fr) | 2006-05-18 | 2014-11-12 | Boston Scientific Limited | Dispositifs médicaux comprenant des zones polymériques à base de copolymère blocs d'éther vinylique |
EP2386322A2 (fr) | 2006-07-03 | 2011-11-16 | Hemoteq AG | Fabrication, procédé et utilisation de produits médicaux libérant un agent actif pour le maintien ouvert permanent de vaisseaux sanguins |
EP2636416A2 (fr) | 2006-07-07 | 2013-09-11 | Abbott Cardiovascular Systems Inc. | Revêtements à base de copolymère séquencé à séparation de phase pour des dispositifs médicaux implantables |
US20140207061A1 (en) | 2006-11-14 | 2014-07-24 | Boston Scientific Scimed, Inc. | Medical Devices and Related Methods |
US8425459B2 (en) | 2006-11-20 | 2013-04-23 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent |
WO2008076345A1 (fr) | 2006-12-14 | 2008-06-26 | Interface Biologics Inc. | Macromolécules modificatrices de surface à fortes températures de dégradation et leur utilisation |
US20150045877A1 (en) | 2006-12-15 | 2015-02-12 | Abbott Cardiovascular Systems Inc. | Regional delivery of therapeutic agents for the treatment of vascular diseases |
CA2673991A1 (fr) | 2007-01-21 | 2008-07-24 | Hemoteq Ag | Procedes d'enrobage de ballonnets de catheters avec une quantite definie d'un agent actif |
US20080279911A1 (en) | 2007-05-11 | 2008-11-13 | Boston Scientific Scimed, Inc. | Medical devices having crosslinked polymeric surfaces |
US20090076595A1 (en) | 2007-09-14 | 2009-03-19 | Boston Scientific Scimed, Inc. | Medical devices having bioerodable layers for the release of therapeutic agents |
WO2009043174A1 (fr) | 2007-10-05 | 2009-04-09 | Interface Biologics Inc. | Polymères réticulés oligofluorés et leurs utilisations |
US20110091508A1 (en) | 2007-10-05 | 2011-04-21 | Interface Biologics ,Inc. | Oligofluorinated cross-linked polymers and uses thereof |
US20110104228A1 (en) | 2007-10-19 | 2011-05-05 | Interface Biologics, Inc | Self-eliminating coatings |
US20180028721A1 (en) | 2007-10-19 | 2018-02-01 | Interface Biologics, Inc. | Self-eliminating coatings |
WO2009049426A1 (fr) | 2007-10-19 | 2009-04-23 | Interface Biologics Inc. | Revêtements autodégradables |
WO2009129385A1 (fr) | 2008-04-16 | 2009-10-22 | Abbott Laboratories | Lipides cationiques et utilisations de ceux-ci |
US20140288497A1 (en) | 2008-05-01 | 2014-09-25 | Bayer Pharma Aktiengesellschaft | Catheter Balloon Drug Adherence Techniques and Methods |
WO2010025398A1 (fr) | 2008-08-28 | 2010-03-04 | Interface Biologics Inc. | Biuret thermiquement stable et macromolécules à base d’isocyanurate modificatrices de surface et leurs utilisations |
US20110295200A1 (en) | 2009-01-09 | 2011-12-01 | Ulrich Speck | Drug-eluting medical device |
WO2010111232A9 (fr) | 2009-03-23 | 2011-03-03 | Micell Technologies, Inc. | Dispositif médical d'administration de médicament |
US20100272774A1 (en) | 2009-04-28 | 2010-10-28 | Surmodics, Inc. | Devices and methods for delivery of bioactive agents |
US20100286608A1 (en) | 2009-05-07 | 2010-11-11 | Biotronik Vi Patent Ag | Drug-coated balloon catheter and method for the production thereof |
US20150196690A1 (en) | 2009-12-11 | 2015-07-16 | Abbott Cardiovascular Systems Inc. | Coatings with tunable molecular architecture for drug-coated balloon |
US20130142834A1 (en) * | 2009-12-18 | 2013-06-06 | Interface Biiologics, Inc. | Local delivery of drugs from self assembled coatings |
US20190298889A1 (en) | 2009-12-18 | 2019-10-03 | Interface Biologics, Inc. | Local delivery of drugs from self assembled coatings |
US10195311B2 (en) | 2009-12-18 | 2019-02-05 | Interface Biologics, Inc. | Local delivery of drugs from self assembled coatings |
US8900603B2 (en) | 2009-12-18 | 2014-12-02 | Interface Biologics, Inc. | Local delivery of drugs from self assembled coatings |
WO2011072398A1 (fr) | 2009-12-18 | 2011-06-23 | Interface Biologics, Inc. | Administration locale de médicaments à partir de revêtements auto-assemblés |
US20150283304A1 (en) | 2009-12-18 | 2015-10-08 | Interface Biologics, Inc. | Local delivery of drugs from self assembled coatings |
CA2793832A1 (fr) | 2010-03-25 | 2011-09-29 | Lixiao Wang | Revetements liberant un medicament pour dispositifs medicaux |
WO2011147408A2 (fr) | 2010-05-27 | 2011-12-01 | Hemoteq Ag | Produit médical revêtu d'une couche non particulaire de libération de principe actif |
EP2531229B1 (fr) | 2010-05-27 | 2014-12-31 | Hemoteq AG | Produit médical revêtu d'une couche non particulaire de libération de principe actif |
US20130245058A1 (en) | 2010-05-27 | 2013-09-19 | Erika Hoffmann | Medical product with a particle-free coating releasing an active substance |
US20130123695A1 (en) | 2010-05-27 | 2013-05-16 | Hemoteq Ag | Balloon catheter coated with an anti-restenotic active ingredient and a molecular dispersion agent that promotes transport |
US20120165786A1 (en) | 2010-06-30 | 2012-06-28 | Chappa Ralph A | Lipid coating for medical devices delivering bioactive agent |
US20130190689A1 (en) | 2011-05-20 | 2013-07-25 | Surmodics, Inc. | Delivery of coated hydrophobic active agent particles |
US20120296274A1 (en) | 2011-05-20 | 2012-11-22 | Surmodics, Inc. | Delivery of coated hydrophobic active agent particles |
US20150140107A1 (en) | 2011-05-20 | 2015-05-21 | Surmodics, Inc. | Delivery of hydrophobic active agent particles |
US20140350522A1 (en) | 2011-07-15 | 2014-11-27 | Micell Technologies, Inc. | Drug delivery medical device |
US20150250926A1 (en) | 2011-10-18 | 2015-09-10 | Micell Technologies, Inc. | Drug delivery medical device |
US20140004253A1 (en) | 2012-06-28 | 2014-01-02 | Covidien Lp | Post-processing of a medical device to control morphology and mechanical properties |
US20150231308A1 (en) | 2012-07-10 | 2015-08-20 | Bayer Pharma Aktiengesellschaft | Catheter with drug coating |
US9206283B1 (en) | 2013-03-15 | 2015-12-08 | Angiodynamics, Inc. | Thermoplastic polyurethane admixtures |
WO2015070814A1 (fr) | 2013-11-15 | 2015-05-21 | 微创心脉医疗科技(上海)有限公司 | Ballonnet à élution médicamenteuse et procédé de fabrication |
US20150209555A1 (en) | 2014-01-24 | 2015-07-30 | Covidien Lp | Coatings for medical devices |
WO2015112348A1 (fr) | 2014-01-24 | 2015-07-30 | Covidien Lp | Revêtements pour dispositifs médicaux |
Non-Patent Citations (32)
Also Published As
Publication number | Publication date |
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EP3796948A4 (fr) | 2022-03-02 |
US20200188560A1 (en) | 2020-06-18 |
US20220362440A1 (en) | 2022-11-17 |
JP2021531061A (ja) | 2021-11-18 |
WO2019222843A1 (fr) | 2019-11-28 |
EP3796948A1 (fr) | 2021-03-31 |
CN112638436A (zh) | 2021-04-09 |
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